How to become a scientist

This post was first published in Jump! an online magazine for pre-teen girls.

Science is fun

What scientists do on holiday

To become a scientist you must first, take an enquiring mind, blend it with some passion, sprinkle on some creativity. Mix it up a bit, and squirt it out in big, loud dollops for everyone to see.

Science is not just for geeks and nerds. It’s not only for boys, or girls, who wear glasses. It’s for those of us with freckles and dimples and turned-up noses. Science is for animal lovers, tongue-rollers, bird-watchers, and teddy bear vets everywhere.

You see science is the world. And we are the world. So science is us, humans.

I love all science, but I especially love human science. The kind of science that looks under your skin, inside your cells, and zooms in, right down to your genes. This is what makes us human, and each one of us is unique and exciting.

I became a scientist because I was inspired to by a biology teacher at school. She asked me to help her clear out the cupboard in the lab. What we didn’t find in there. And lurking at the back, in a dark jar, was the most gorgeous pig foetus. We changed the preserving fluid, to reveal the tiny, perfect animal; when was he put in there, kept for me to find? I was hooked.

At university I studied human anatomy. I was able to study bodies donated to medical research, to look inside each and every part of the body, to learn where everything goes and how everything fits perfectly together. We prepared glass slides of the microanatomy too. We studied how the cells in the body connect to each other and to the rest of the body. It was fascinating study.

In my work since, I have used this knowledge of the human body every day. Every single experiment we carry out, is done in the knowledge that someday, somewhere, someone will one day benefit from the work we are doing to find out more about the genes which control all aspects of human life and variety.

Interested?

If you want to read a bit more, the next two sections are more advanced, but I’m sure you’ll be able to follow.

DNA unwound

DNA is fascinating. I have spent nearly twenty years getting inside this dynamic molecule, the basic component of human life, that controls hair colour and how long you will live and everything in between.

Laboratory analysis of DNA

Every cell in the human body contains this miracle molecule. It's wound up inside the nucleus and can respond to our changing environment. For example, in work I have recently completed, I have been able to measure the rate of response of DNA to conditions mimicking inflammation in the wall of the peripheral blood vessels. Put simply, I created a laboratory model of atherosclerosis, which as you know is a thickening of the arteries, leading to heart attack and stroke. These experiments were important to do because they showed us how the DNA functions in cells from individual people with different DNA variations.

DNA is divided into functional regions, which we call genes. These genes contain naturally occurring variations, which makes us different from one another. Many of these variants are completely compatible with normal life; that is, the cell will grow and divide in the normal way. This is different from mutations such as those in cancerous cells, which cause aberrant cell proliferation and division.

In order for a region of DNA to respond to a signal from outside the cell, it must be in a relaxed or open state. A number of carrier or transport molecules including cytokines are responsible for presenting the stimulus to the open DNA molecule, in the correct functional position or gene. Once this has happened, the region of DNA closes, a bit like pushing a spring between your hands. In this closed the position, the function of the gene is turned off and no other molecules can interact with the DNA. Imagine a very fine orchestra with a very busy conductor making sure that nothing goes out of tune. All these processes happen without our conscious intervention, and that is what makes DNA fascinating.

Human macrophages, from white blood cells

Techniques developed in the laboratory by some very clever scientists have allowed us to visualise these processes. We can measure them and discern differences in them between different people, who have different gene variants. Thus, we can say that genetics can determine an individual's response to inflammation. But what do we do with this information. Well, in the not too distant future scientists would like to translate this research into the clinical setting so that family and hospital doctors may be able to look at our genetics when deciding on treatment.

Cellular communication

No, nothing to do with a cell phone, because before mobiles or cell phones there was a time when this only meant cell to cell interaction within an organ or tissue. This important cellular behaviour drives diverse functions from contracting myocytes in heart muscle to effecting action potentials in nerves.

We can visualise these fascinating events in the laboratory ex vivo (in cells outside of a living body). For example, immortalised cardiac myocytes (heart muscle cells kept alive) can be cultured in a monolayer in a petri dish. A stimulant introduced into a single cell causes that cell to contract. This stimulates the adjacent cell to contract, and so on, mimicking the heartbeat. This can be seen microscopically and contributes to our better understanding of the function of this important tissue.

Cross section through mitochondrion,
a part of the cell which makes energy

Similarly, action potentials in nervous tissue can be measured and studied by subjecting ultra-thin sections of tissue to chemical modulators in solution. Sensitive electrophysiology equipment detects the release of neurotransmitters from neurons in the tissue slice and complex algorithms translate this effect into an audible thump. It's really amazing to hear this happening in the lab, these are very elegant experiments indeed.

A different kind of communication is seen in the immune system, where antigen-presenting cells identify foreign bodies, such as bacteria, and 'show' them to the T lymphocyte cells which effect an immune response. Where this system is compromised or overwhelmed, an infection can set in, for example pneumonia, which requires a trip to the doctor for antibiotics.

And who said biology was just a pretty face?

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I'm not a sceptic, I'm a scientist

I read the papers every day and I never cease to be amazed at the total lack of credibility of the health stories. This is across all the papers, because it's what we, the public, are told it's what we want to read. Well, it's not what I want to read. And I believe that many of us glance through the stories and then get on with our balanced diet, with a bit of exercise and a healthy, positive approach to life. Or do we? I'd like to think so, but the sheer volume of these stories mean that at some point, we're going to stop and read on and give them more than a cursory perusal.

Two such stories caught my eye this morning. The first is about a diet based on our genes. To be specific, a genetic test based on the normal variation of seven genes. These seven genes out of thousands of genes have been picked because of their role in metabolism and were decided upon by researchers working on diabetes type 2. Diabetes is a serious health condition and genetically speaking is a complex multi-factorial disease. That means that it's not just what you do or don't eat, it also depends on your genetic make-up and how your genes interact with your environment (I have written more on this here). And there are certainly more than seven genes involved. A lovely blonde woman is shown as having lost loads of weight and, they say, dieters using this diet have kept the weight off. Isn't it more likely that people who are supported and encouraged on diets in these studies have more success at weight loss than those who diet on there own?

The second story is a re-hash of the old don't eat processed meat story, you'll get cancer. We know. But a bacon sandwich or a sausage roll occasionally is both delicious and can be part of a balanced diet. We are enlightened enough to understand the health disadvantages of eating a high fat, processed food diet, but it is after all our choice. And I choose to eat bacon if I want to, I don't eat it every day. I also eat broccoli and oily fish and brazil nuts for selenium. And I may or may not get cancer or heart disease.

The point is, we have made huge advances in genetics but we do not know everything about how our genes work. It is something that has potential in science and medicine and I wholly support the scientific study in this area. But please don't give up a healthy, balanced lifestyle in the hope that nothing bad will ever happen to you. 

Follow @Shackleford_LB

I'm not a sceptic, I'm a scientist

I read the papers every day and I never cease to be amazed at the total lack of credibility of the health stories. This is across all the papers, because it's what we, the public, are told it's what we want to read. Well, it's not what I want to read. And I believe that many of us glance through the stories and then get on with our balanced diet, with a bit of exercise and a healthy, positive approach to life. Or do we? I'd like to think so, but the sheer volume of these stories mean that at some point, we're going to stop and read on and give them more than a cursory perusal.

Two such stories caught my eye this morning. The first is about a diet based on our genes. To be specific, a genetic test based on the normal variation of seven genes. These seven genes out of thousands of genes have been picked because of their role in metabolism and were decided upon by researchers working on diabetes type 2. Diabetes is a serious health condition and genetically speaking is a complex multi-factorial disease. That means that it's not just what you do or don't eat, it also depends on your genetic make-up and how your genes interact with your environment (I have written more on this here). And there are certainly more than seven genes involved. A lovely blonde woman is shown as having lost loads of weight and, they say, dieters using this diet have kept the weight off. Isn't it more likely that people who are supported and encouraged on diets in these studies have more success at weight loss than those who diet on there own?

The second story is a re-hash of the old don't eat processed meat story, you'll get cancer. We know. But a bacon sandwich or a sausage roll occasionally is both delicious and can be part of a balanced diet. We are enlightened enough to understand the health disadvantages of eating a high fat, processed food diet, but it is after all our choice. And I choose to eat bacon if I want to, I don't eat it every day. I also eat broccoli and oily fish and brazil nuts for selenium. And I may or may not get cancer or heart disease.

The point is, we have made huge advances in genetics but we do not know everything about how our genes work. It is something that has potential in science and medicine and I wholly support the scientific study in this area. But please don't give up a healthy, balanced lifestyle in the hope that nothing bad will ever happen to you. 

Follow @Shackleford_LB

RNA unplugged

I love this molecule. It is so clever. Where DNA writes the code for our genes, it is RNA which does all the hard work. RNA molecules perform many functions and exist in pre-cursor form as well as spliced, alternatively spliced or even shortened or degraded molecules. All of these are important controls in gene expression and each gene will have it's own RNA processing. But in it's basic form, RNA is transcribed from DNA, a process in which introns of the gene sequence are removed from the final molecule leaving only the functional or coding sequences.

Of course, it's often more complex than that, and there are some very elegant experiments to demonstrate this. So let's concentrate on a more simple experiment that I have worked on extensively. Using a method devised by Chomzynski in 1987, molecular biologists can extract RNA from living cells. As these cells are living and performing all their normal functions, it is possible therefore to get a 'snapshot' of gene activity at the moment the nuclear material is extracted. In this method, total RNA is extracted. This includes tRNA, rRNA and mRNA. I'll continue with mRNA ,or messenger RNA, and come back to the others in another blog.


mRNA is a short-lived molecule. This means that when genes are activated and transcribed, mRNA is then available to be translated into a functional protein. Proteins are made up of blocks of amino acids which confer activity and functionality to the molecule, such as enzymes, hormones and cytokines. But first, it is possible to measure gene expression (activity) in cells and tissues by a method known as real time PCR. For a description of how PCR works see this iconic work by Kary Mullis. *A lot of good work was done in the late 80's, Peter!*


In a clever twist, we can reverse transcribe the mRNA extracted from cells into cDNA, which is simply DNA without introns. Then we use real time PCR to quantitate the amount of gene expression in the sample, relative to a known amount of gene expression. This is a very sensitive method of gene expression, using very small amounts of material, so we can measure large numbers of genes in multiple cells and tissues.
We are interested in gene expression because we know that variations in the genetic code can lead to changes in gene expression, which in turn affects protein production, and this may manifest itself in the body, as shown in diverse conditions from cancer to heart disease and cystic fibrosis in between. All clear?


Well, not entirely. This is true for many genes, but we have been working on a gene for which no protein has been identified, but which is strongly associated with increased risk of cardiovascular disease. This gene is known as a non-coding RNA gene, but how does it influence cardiovascular disease risk? The fact is, we still don't quite know, although we do know a lot about the gene. It seems that the RNA from this gene influences the expression of other genes, particularly cell cycle genes, thereby affecting cell proliferation. If this happens within the arteries around your heart, it could lead to abnormal thickening or inflammation of the artery wall, resulting in a heart attack.


So when you are thinking about complex multifactorial conditions, remember that RNA plays it's part, too.

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I met a man who asked me about quantum mechanics of DNA...

Not your standard black tie dinner party conversation, Jonathan, but I can talk about anything. Of course DNA structure and function are governed by the laws of physics, bonds must be obeyed, physical restraints respected, spatial integrity maintained. That's at the very heart of chromatin remodelling. Now, I had planned to write next about RNA, but this conversation reminded me that most amateur molecular biologists imagine that DNA is a linear molecule and everything happens along a long, flat line. That's not true. Firstly, you should all know that DNA is in fact double-stranded. Secondly, the bonds between the bases cause a torsion or twist, known as the helix. The entire double-stranded DNA helix is further wound around histones (ordered clumps of proteins), which adds another layer of constraint. And all of this is packed into the nucleus of the cell. Brilliant!

But here's the interesting bit. I have looked at the this very aspect of molecular modelling (biologist speak) or quantum physics (geek speak) using atomic force microscopy. This technique allows the researcher to obtain a topographical image of the DNA molecule undergoing re-modelling; I can see a region of DNA 'open' or 'close' varying only by a single base change in the sequence. This very simple variation in DNA sequence therefore changes the molecular stoichiometry, which affects DNA folding and the accessibility of the gene to factors which promote gene transcription (I promise we'll get to that in the next blog entry). Furthermore, these topographical changes can be predicted using folding software, which helps inform biologists about the type of experiments we should be doing to further elucidate the mysteries of the DNA molecule. Important, I think you'll agree?

And finally, I remember that a Professor I know has published a useful book, which I think I'll have another look at now. To be continued....

Follow @Shackleford_LB

DNA unwound

DNA is fascinating. I have spent nearly twenty years getting inside this dynamic molecule, the basic component of human life, that controls hair colour and how long you will live and everything in between.

Every cell in the human body contains this miracle molecule. It's wound up inside the nucleus and can respond to our changing environment. For example, in work I have recently completed, I have been able to measure the rate of response of DNA to conditions mimicking inflammation in the wall of the peripheral blood vessels. Put simply, I created a laboratory model of atherosclerosis, which as you know is a thickening of the arteries, leading to heart attack and stroke. These experiments were important to do because they showed us how the DNA functions in cells from individual people with different DNA variations.

DNA is divided into functional regions, which we call genes. These genes contain naturally occurring variations, which makes us different from one another. Many of these variants are completely compatible with normal life; that is, the cell will grow and divide in the normal way. This is different from mutations such as those in cancerous cells, which cause aberrant cell proliferation and division.

In order for a region of DNA to respond to a signal from outside the cell, it must be in a relaxed or open state. A number of carrier or transport molecules including cytokines are responsible for presenting the stimulus to the open DNA molecule, in the correct functional position or gene. Once this has happened, the region of DNA closes, a bit like pushing a spring between your hands. In this closed the position, the function of the gene is turned off and no other molecules can interact with the DNA. Imagine a very fine orchestra with a very busy conductor making sure that nothing goes out of tune. All these processes happen without our conscious intervention, and that is what makes DNA fascinating.

Techniques developed in the laboratory by some very clever scientists have allowed us to visualise these processes. We can measure them and discern differences in them between different people, who have different gene variants. Thus, we can say that genetics can determine an individual's response to inflammation. But what do we do with this information. Well, in the not too distant future scientists would like to translate this research into the clinical setting so that family and hospital doctors may be able to look at our genetics when deciding on treatment.

Next time, RNA unplugged and proteins unmixed.

Follow @Shackleford_LB